Project Summary Parkinsonism (PS) is a debilitating neurodegenerative disorder that affects millions of people worldwide. The causes of primary (idiopathic) PS are largely unknown, although there is growing experimental and epidemiologic evidence that environmental toxicants play important etiologic roles. Endotoxin (lipopolysaccharide) is a component of the outer membranes of Gram-negative bacteria cell walls that is released when bacteria lyse. Human exposure to endotoxin occurs in numerous environmental settings, with especially high levels found in cotton textile manufacturing, which is the focus of this proposed research. It is noteworthy that endotoxin has been established as a model experimental agent that induces selective death of dopaminergic neurons in vitro and in vivo. Despite convincing experimental support for a plausible pathogenic role of endotoxin in PS, there have been no previous epidemiologic studies that have explicitly tested this association. Accordingly, we are proposing to conduct an epidemiological study of PS among a well-characterized cohort of women textile workers in Shanghai, China that we have studied previously for cancer risk factors. Our previous research has generated quantitative estimates of cumulative doses of endotoxin. We will conduct standardized neurological examinations to determine the prevalence and severity of the cardinal signs and symptoms of parkinsonism among 600 retired women previously employed in cotton textile factories who were exposed to endotoxin and an age-matched non-exposed group composed of 300 retired women textile workers who had never worked in cotton factories or in jobs with potential endotoxin exposure. We will also perform a 3-year clinical follow-up among PS cases identified in years 1 and 2 of the project to determine disease progression. Our analyses will generate quantitative dose-response trends for relations of endotoxin exposure with PS risk, severity, and progression that are adjusted for potential confounding by age, smoking, reproductive history, and other occupational exposures. The findings from this project have great promise to clarify further the role of neuroinflammation in the pathogenesis of human parkinsonism, which will ultimately be important for prevention of this disorder.